Escherichia coli that produce plasmid-mediated AmpC beta-lactamases are rare in the United States. The clinical features associated with infection with these organisms have not been well described. We identified 2 clinical isolates of E. coli that produced the plasmid-mediated AmpC enzyme beta-lactamase CMY-2. These organisms were recovered from urine specimens and were resistant to ceftazidime, ceftriaxone, and cefepime. One isolate was resistant to ertapenem but susceptible to imipenem and meropenem; the other was susceptible to imipenem, meropenem, and ertapenem. One of the 2 infected patients did not require specific therapy; the other required imipenem for cure. The presence of the CMY-2 beta-lactamase was confirmed by DNA sequencing. Hybridization studies confirmed that the bla(CMY-2) gene was on a plasmid in both isolates; in one of them, the probe also hybridized with chromosomal DNA. Infection with plasmid-mediated AmpC beta-lactamases in E. coli in the United States may be associated with treatment failure, and these strains may become a serious nosocomial threat.